Abstract
Tumor-associated macrophages participate in the complex network of support that favors tumor growth. Among the various strategies that have been developed to target these cells, blockade of the CSF-1R receptor is one of the most promising one. Here, we characterize the resulting state of human macrophages exposed to a CSF-1R kinase inhibitor. We find that CSF-1R receptor inhibition in human macrophages is able to impair cholesterol synthesis, fatty acid metabolism and hypoxia-driven expression of dihydropyrimidine dehydrogenase, an enzyme responsible for the 5-fluorouracil macrophage-mediated chemoresistance. We show that this inhibition of the CSF-1R receptor leads to a downregulation of the expression of SREBP2, a transcription factor that controls cholesterol and fatty acid synthesis. We also show that the inhibition of ERK1/2 phosphorylation resulting from targeting the CSF-1R receptor destabilizes the expression of HIF2α in hypoxia resulting in the downregulation of dihydropyrimidine dehydrogenase expression restoring the sensitivity to 5-fluorouracil in colorectal cancer. These results reveal the unexpected metabolic rewiring resulting from the CSF-1R receptor targeting of human macrophages in tumors.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Team Mechanobiology, Immunity and Cancer, Institute for Advanced Biosciences Building Albert Bonniot Boulevard de la Chantourne 38700 La Tronche France
The authors declare no conflicts of interest.
In this new version, we have corrected typos. We have also combined each subfigures on one figure file to ease the reading. We have replaced figure 2H with a more appropriate figure for th western blot and replaced figure 5 with a new figure containing appropriate controls that were lacking on the previous version.